Liver injury and disease progression are thought to be driven by host immune responses in both infections, but disease progression is not linear over time. Slow and fast progressors have been identified among HCV-infected patients, and distinct phases of disease severity and disease progression are noted in HBV-infected patients. In previous studies we had extensively characterized the innate and adaptive immune responses in liver and blood of HCV-infected patients. However, due to its unique anatomy and location the liver is also exposed gut-derived bacteria and their products that enter via the portal vein. The relative contribution of microbial products and virus-induced cytokines to the activation of innate immune cells in the liver and to inflammation and severity of liver disease are not known. We are therefore interested in the regulation of intrahepatic immune responses via the gut-liver axis. In the context of a clinical study, we are currently analyzing the activation and function of human innate immune cells in the three compartments of the gut-liver axis: systemic blood, portal vein blood and liver. This work is conducted in collaboration with Dr. Heller. In addition, we are using mouse models to study the influence of defined gastrointestinal microbiota on systemic immune responses and the outcome of viral infections. A fast growing body of literature arising over the past few years demonstrated that commensal bacteria, in particular those of the gastrointestinal tract, are indispensible not only for digestion and metabolism, but also for the development and regulation of local and systemic immune responses. The identification of beneficial host-microbe interactions and the characterization of their immunomodulatory mechanisms are necessary to understand the regulation of intrahepatic and systemic immune responses in health and disease.